The production of 2-acyl-4-oxo-chromenes (2-acylchromones) by ring closure or substituted benzene ring structures are well known in the art. One known initial process step for the production of 4-oxochromene-2-carboxylic acid, or derivatives of such acids including acid halides or esters, uses 2-hydroxy-acetophenone compounds as starting materials. (See e.g., J. Med. Chem., Vol. 15, No. 8, 1972.) The reaction scheme to produce the 2-carboxylic acid and esters is as follows: where X is ethyl, for example. The acid can be converted to an acyl halide, such as acyl chloride, instead of the ethyl ester by reacting it with SOCl2, for example. A further reaction of the acyl chloride with NH3 can be used to produce the carboxamide.
The above chromene-derivative compounds have been reported as useful intermediates for the production of compounds wherein the phenyl ring of the chromene ring structure is further substituted by a benzoylamino derivative to produce antidepressants. See, for example, U.S. Pat. No. 5,659,051.
One synthesis of racemic 2-(chroman4-one-2-yl)acetic acid derivatives begins with treating a coumarin derivative with a reducing agent such as diisoamylborane, lithium tri-butoxyaluminohydride, lithium triethylborohydride, lithium trimethoxyaluminium hydride, sodium borohydride, H2/Pd/C, or the like. The reagent and reaction conditions may be selected to reduce either the α,β-double bond to the alkane, or the lactone to a lactol, or both. In a preferred aspect of the invention, lithium tri-butoxyaluminohydride, LiAlH4 is used to reduce the lactone at the 2-position to a lactol.
The lactol hydroxyl group may be converted into a carboxymethyl group by standard chain extension/replacement reactions. For example, treating the lactol with chloroacetate under basic conditions, for example in the presence of pyridine, results in a carboxymethyl group at the 2-position.